CN102319215B - Vecuronium bromide liposome injection - Google Patents
Vecuronium bromide liposome injection Download PDFInfo
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- CN102319215B CN102319215B CN 201110282746 CN201110282746A CN102319215B CN 102319215 B CN102319215 B CN 102319215B CN 201110282746 CN201110282746 CN 201110282746 CN 201110282746 A CN201110282746 A CN 201110282746A CN 102319215 B CN102319215 B CN 102319215B
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Abstract
The invention discloses a vecuronium bromide liposome injection and a preparation method thereof. The liposome injection is prepared from vecuronium bromide, cholesterol, phosphatidyl ethanolamine, soyabean lecithin, twain 80, trehalose, mannitol and polyvinylpyrrolidone in a specific weight ratio. The liposome injection has high preparation stability, and the liposome is not cracked due to fusion, ice crystals and the like in the refrigerating process and keeps high entrapment efficiency even after being stored for a long-time. Due to the adoption of the injection, the solubility of the vecuronium bromide is improved, the quality of a preparation product is improved, toxic and side effects are reduced, the retention time of a medicament is increased during systemic circulation, the bioavailability of the medicament is enhanced, the curative effect is improved remarkably; and moreover, the preparation method is simple and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of lipidosome injection and method for making thereof, be specifically related to a kind of vecuronium bromide lipidosome injection and method for making thereof, belong to medical technical field.
Background technology
Vecuronium bromide, chemical name are bromination 1-[3 α, 17 β-diacetoxy-2-β (piperidino)-5 α-androstane-16 beta-yl]-the 1-methyl piperidine, molecular weight 637.73, structural formula is as follows:
Vecuronium bromide is the loose shape thing of white or off-white color, and is slightly water-soluble, is soluble in dichloromethane, almost insoluble in dehydrated alcohol.
Vecuronium bromide is the two amino androstane class muscle relaxants of a kind of novel non depolarization, is used for endotracheal intubation, and anesthesia is kept, and is the liquor-saturated adjuvant drug of a kind of general anesthesia, can promote skeletal muscle lax.Rapid-action behind its quiet notes, without separating the cardiac vagal effect, do not discharge histamine, the cardiovascular function quite stable is applicable to myocardial ischemia and heart patient; Less through renal excretion again, can be next compensatory by the liver elimination during renal failure, so the renal failure patient can use.Structure is similar to pancuronium bromide, by and acetylcholine competition at the nicotinic receptor of striomotor soleplate and the conduction between block nerves tip and the striped muscle.With the depolarization neuromuscular blocking drug, different such as succinylcholine, this product does not cause the vibration of muscle fiber bunchy.
The vecuronium bromide dosage form of listing is mainly injection and freeze-dried powder at present, the vecuronium bromide injection that common process is prepared, the physics and chemistry stable in properties is poor, and the long-term storage drug quality can descend but also can generate some impurity, bring toxic and side effects, stayed hidden danger for clinical use.The freeze-dried powder fabrication cycle is long, and expense is high, price.
Patent CN101843593A discloses a kind of injection freeze-dried powder and preparation process, it prepares with vecuronium bromide, aminoacid or polysaccharide, Polyethylene Glycol, vitamin E and glycerol, but aminoacid is unstable, can accelerate the unstability of medicine, and has increased cost of manufacture.
In the pharmaceutical carrier induction system, the research of the submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become field very active in the novel pharmaceutical formulation research.Drug encapsulation can be changed medicine distribution in vivo in these submicrons, increase medicine in the abundance of target organ, thereby improve curative effect, alleviate toxic and side effects.
In targeting drug delivery system, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages:
(1) have slow releasing function: active component slowly discharges, and delays renal excretion and metabolism, thereby prolongs action time, improves mass effect;
(2) reduce drug toxicity;
(3) dissolubility of increase medicine improves the quality of the pharmaceutical preparations;
(4) have targeting: the contained medicine of liposome is kept high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting;
(5) has protective effect to active pharmaceutical ingredient.
Liposome (Liposome) is dispersed in water phospholipid by British scholar Bangham and Standlish at first and finds when carrying out electron microscopic observation.Phospholipid is dispersed in water the self-assembling formation multilamellar vesicle, every layer of equal bilayer of lipid not; Separated by water between vesicle central authorities and each layer, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called liposome.Liposome can be divided into multilamelar liposome and courage and insight liposome.Unilamelar liposome is divided into again small unilamellar vesicle and large unilamellar vesicle.Small unilamellar vesicle is spherical, and size is generally the 20-50 nanometer; Large unilamellar vesicle is of a size of the micron number magnitude.
The people such as Britain Lai Men in 1971 begin liposome is used for pharmaceutical carrier, Main Function mechanism is drug powder or solution are wrapped in the aqueous phase that the liposome bilayer lipid membrane seals or embed in the liposome bilayer lipid membrane, this microgranule has the class cellularity, enter the interior principal agent of human body is activated body by reticuloendothelial system phagocytic autoimmune function, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, put aside in the histoorgan such as lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
In recent years, continuous progress along with biotechnology, liposome preparation technology gradual perfection, the liposome mechanism of action is further illustrated, liposome is fit to vivo degradation, avirulence and non-immunogenicity in addition, particularly great number tested data proof liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces the advantage such as drug dose.
Because there is demand in the deficiency of vecuronium bromide injection for the vecuronium bromide lipidosome injection at present.
Summary of the invention
In order to form colory vecuronium bromide lipidosome injection, can good compatible with vecuronium bromide it well be sealed and non-leakage filmogen thereby importantly seek, and seek the excipient composition that can make liposome form the stable injectable agent.
To achieve these goals, large quantity research and realization that the inventor carries out, find the vecuronium bromide of specified weight proportioning, cholesterol, PHOSPHATIDYL ETHANOLAMINE, soybean phospholipid, Tween 80, trehalose and PVP can make the vecuronium bromide lipidosome injection, wherein, envelop rate as the vecuronium bromide of active constituents of medicine is high, the liposome particle diameter is little and be evenly distributed, compare with vecuronium bromide injection of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in the body circulation, the biocompatibility of medicine is high, bioavailability obviously improves, and curative effect obviously improves.
On the one hand, the invention provides a kind of vecuronium bromide lipidosome injection, it is mainly made by the composition of following weight proportion:
Preferably, vecuronium bromide lipidosome injection of the present invention is mainly made by the composition of following weight proportion:
Preferably, weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soybean phospholipid are 1: 1-1: between 2, further preferably, weight sum and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE of cholesterol and soybean phospholipid are 1: 1-3: between 4.
Further preferably, vecuronium bromide lipidosome injection according to the present invention is made by the medicine that comprises following weight proportion and excipient composition:
Preferably, the weight sum of cholesterol and soybean phospholipid and the weight ratio between the PHOSPHATIDYL ETHANOLAMINE are 1: 1.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.In the present invention, as the vecuronium bromide of active constituents of medicine, its poorly water-soluble is fat-soluble good.For the characteristics of vecuronium bromide, the inventor finds that by research PHOSPHATIDYL ETHANOLAMINE is particularly suitable for as basic phospholipid filmogen.
PHOSPHATIDYL ETHANOLAMINE (phosphatidyl ethanolamine, PE) is as a kind of natural phospholipid, and its content is very high, obtains easily, and is cheap.The phase transition temperature of PHOSPHATIDYL ETHANOLAMINE is higher, is easy to form stable liposome membrane.
In vecuronium bromide lipidosome injection of the present invention, for the vecuronium bromide of 4 weight portions, the consumption of PHOSPHATIDYL ETHANOLAMINE is the 50-200 weight portion.If the consumption of PHOSPHATIDYL ETHANOLAMINE is lower than 50 weight portions, then can't form stable liposome; Otherwise if the consumption of the consumption of PHOSPHATIDYL ETHANOLAMINE is higher than 200 weight portions, then the envelop rate as the vecuronium bromide of active constituents of medicine descends, and the quality of injection and curative effect reduce.
In vecuronium bromide lipidosome injection of the present invention, the collaborative membrane stability that is used for regulating liposome of cholesterol and soybean phospholipid.
The inventor finds through research, when weight sum and the PHOSPHATIDYL ETHANOLAMINE weight ratio of cholesterol and soybean phospholipid is 1: 1-1: in the time of 2, can form stable vecuronium bromide liposome.When the weight sum of cholesterol and soybean phospholipid and PHOSPHATIDYL ETHANOLAMINE weight ratio were lower than 1: 1, membrane stability reduced, and vecuronium bromide is easy to seepage; When the weight sum of cholesterol and soybean phospholipid and PHOSPHATIDYL ETHANOLAMINE weight ratio were higher than 1: 2, vecuronium bromide liposome membrane flowability was too high, and the vecuronium bromide that is wrapped in the liposome is easy to discharge.In addition, research finds, when weight sum and the PHOSPHATIDYL ETHANOLAMINE weight ratio of cholesterol and soybean phospholipid is 1: 1-1: in the time of 2, formed liposome toxicity is low.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of vecuronium bromide lipidosome injection of the present invention is high, is to cause one of high factor of drug bioavailability.
On the other hand, the inventor studies discovery, in vecuronium bromide lipidosome injection of the present invention, for the vecuronium bromide of 4 weight portions, the consumption of PHOSPHATIDYL ETHANOLAMINE is the 50-200 weight portion, and cholesterol is the 50-200 weight portion, and soybean phospholipid is the 10-50 weight portion, and the weight sum of cholesterol and soybean phospholipid and PHOSPHATIDYL ETHANOLAMINE weight ratio are 1: 1-1: 2 o'clock, the envelop rate of formed vecuronium bromide lipidosome injection was high.
In vecuronium bromide lipidosome injection of the present invention, further improve the stability of liposome membrane with Tween 80.Tween 80 (polysorbate 80) is a kind of non-ionic surface active agent, when being used for the PHOSPHATIDYL ETHANOLAMINE duplicature, can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of vecuronium bromide lipidosome injection.
In vecuronium bromide lipidosome injection of the present invention, for the vecuronium bromide of 4 weight portions, the consumption of Tween 80 is the 1-60 weight portion.If the consumption of Tween 80 is lower than 1 weight portion, then cause the stability improvement of vecuronium bromide lipidosome injection inadequate owing to its consumption is excessively low, otherwise if the consumption of Tween 80 is higher than 60 weight portions, it is too high and cause liposome membrane to be easy to reveal then to be used for its consumption.
Research finds, when the vecuronium bromide that uses above-mentioned specified quantitative, PHOSPHATIDYL ETHANOLAMINE, cholesterol, soybean phospholipid and Tween 80, can obtain colory vecuronium bromide liposome, and its envelop rate and stability are all very high, and toxicity is low, and bioavailability is high.
In vecuronium bromide lipidosome injection of the present invention, use trehalose, mannitol and polyvinylpyrrolidone as excipient, be further used for forming stable injection.
Trehalose be by two glucose molecules with α, α, 1; the nonreducing sugar that the 1-glycosidic bond consists of; self property is highly stable, and its most obvious character is that the biomembranous ability of protection is arranged under anhydrous condition, even make liposome also keep complete form in the situation of dehydration.
In vecuronium bromide lipidosome injection of the present invention, trehalose can effectively be protected form and the stability of liposome particles, further improves the stability of lipidosome injection.
Polyvinylpyrrolidone (PVP) is macromolecular compound, fusing point is high, dissolubility in water and organic solvent is all good, toxicity is low, physiological compatibility is good, has the effect of dispersion medicine, because its existence can make the water viscosity increase, be encapsulated in the moisture film in the middle of the liposome and make water soluble drug have higher envelop rate, and can make medicine stable in storage.
Mannitol pharmaceutically is being good diuretic, and Lowering the intracranial hypertension, intraocular pressure and treatment kidney medicine, dehydrant, sugar succedaneum, also as the diluent of the excipient of tablet and solid, liquid especially can support for lyophilized injectable powder provide good molding.
Vecuronium bromide lipidosome injection of the present invention, the specification of its vecuronium bromide can be 2mg, 4mg and 10mg.
On the other hand, the present invention also provides a kind of preparation method of vecuronium bromide lipidosome injection, specifically comprises being prepared as follows step:
(1) cholesterol, PHOSPHATIDYL ETHANOLAMINE, soybean phospholipid, Tween 80 are dissolved in an amount of buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of molten condition, add vecuronium bromide, constantly stir lower add trehalose, mannitol and PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, namely gets the vecuronium bromide lipidosome injection.
Preparation method described above, wherein said buffer salt solution are selected from a kind of in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, the borate buffer solution, are preferably pH and are 7.2 phosphate buffered solution.
Preparation method described above, wherein the temperature of the molten condition liposome described in the step (3) is 60 ℃.
Preparation method described above, wherein the pre-freeze temperature is-30～-60 ℃ during the lyophilizing described in the step (4), and the pre-freeze time is 2～5 hours, and the distillation time is 12～48 hours, and baking temperature is 25～35 ℃, be 2～4 hours drying time.
Beneficial effect
The inventor has obtained colory vecuronium bromide lipidosome injection by selecting suitable material composition, adopting suitable preparation technology, and the liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability is high.
Lipidosome injection of the present invention has reduced toxic and side effects, improved the formulation products quality, had good preparation stability, liposome can not break because of dehydration, fusion, ice crystal etc. in the refrigerating process, after the long term storage, liposome keeps good envelop rate equally.
By the vecuronium bromide lipidosome injection that the inventive method makes, improved the dissolubility of vecuronium bromide, improved the quality of formulation products, reduced toxic and side effects, increased the retention time of medicine in the body circulation, improved the bioavailability of medicine, curative effect obviously improves; And preparation method is simple, is suitable for industrialized great production.
Description of drawings
Fig. 1 is the blood drug level-time graph of vecuronium bromide lipidosome injection.
The specific embodiment
Below further specify by specific embodiment the present invention, characteristics of the present invention and advantage will become more clear along with these explanations, these embodiment only are illustrative, and should not be construed as limitation of the present invention.
The preparation of embodiment 1 vecuronium bromide lipidosome injection
Used composition and weight thereof are as follows:
Adopt preparation technology to prepare the vecuronium bromide lipidosome injection:
(1) 120g cholesterol, 150g PHOSPHATIDYL ETHANOLAMINE, 30g soybean phospholipid and 10g Tween 80 are dissolved in 1000ml pH and in 7.2 the phosphate buffered saline, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 4g vecuronium bromide, constantly stir the lower 100g of adding trehalose, 70g mannitol and 80g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-30 ℃, and the pre-freeze time is 5 hours, and the distillation time is 48 hours, and baking temperature is 35 ℃, and be 2 hours drying time, namely gets the vecuronium bromide lipidosome injection.
The preparation of embodiment 2 vecuronium bromide lipidosome injections
Used composition and weight thereof are as follows:
Adopt preparation technology to prepare the vecuronium bromide lipidosome injection:
(1) pH that 75g cholesterol, 100g PHOSPHATIDYL ETHANOLAMINE, 25g soybean phospholipid and 20g Tween 80 is dissolved in 1000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 4g vecuronium bromide, constantly stir the lower 30g of adding trehalose, 30g mannitol and 40g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-60 ℃, and the pre-freeze time is 2 hours, and the distillation time is 12 hours, and baking temperature is 25 ℃, and be 4 hours drying time, namely gets the vecuronium bromide lipidosome injection.
The preparation of embodiment 3 vecuronium bromide lipidosome injections
Used composition and weight thereof are as follows:
Adopt preparation technology to prepare the vecuronium bromide lipidosome injection:
(1) pH that 30g cholesterol, 40g PHOSPHATIDYL ETHANOLAMINE, 10g soybean phospholipid and 10g Tween 80 is dissolved in 1000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 2g vecuronium bromide, constantly stir the lower 10g of adding trehalose, 10g mannitol and 30g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-45 ℃, and the pre-freeze time is 3.5 hours, and the distillation time is 25 hours, and baking temperature is 30 ℃, and be 3 hours drying time, namely gets the vecuronium bromide lipidosome injection.
The preparation of Comparative Examples 1-3 vecuronium bromide lipidosome injection
Composition in will the Comparative Examples 1-3 as shown in following table 1 adopt respectively with embodiment 1-3 in identical production technology, make the vecuronium bromide lipidosome injection:
Raw materials used composition among the table 1 Comparative Examples 1-3
Wherein, "/" expression is not used.
The mensuration of test example 1 liposome particle diameter
Under the room temperature condition, get the vecuronium bromide lipidosome injection among embodiment 1-3 and the Comparative Examples 1-3, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.The results are shown in the following table 2.
Table 2 liposome particle diameter testing result
As known from Table 2, the lipidosome injection particle diameter that embodiment 1-3 makes is even, and is aobvious spherical, big or small homogeneous; The lipidosome injection particle diameter that Comparative Examples 1-3 makes is inhomogeneous, and shape is indefinite, and is not of uniform size.
Particularly, even when adopting same production technology, the particle appearance of gained vecuronium bromide liposome and mean diameter thereof obviously are better than the vecuronium bromide liposome of gained among the Comparative Examples 1-3 among the embodiment 1-3.When the composition beyond using the used composition of the present invention was described, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the outward appearance of gained vecuronium bromide liposome was inferior to the present invention, and mean diameter obviously goes out greatly a lot.
The mensuration of test example 2 envelop rates
With the vecuronium bromide lipidosome injection for preparing among embodiment 1-3 and the Comparative Examples 1-3 rotating speed high speed centrifugation with 5000r/min, centrifugal 20 minutes, get supernatant, use dissolve with methanol, the HPLC method is surveyed vecuronium bromide content, and the computational envelope rate the results are shown in the following table 3.
Table 3 entrapment efficiency determination result
As shown in Table 3, the envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly.When the composition beyond using the used composition of the present invention was described, perhaps when the composition consumption was outside the composition amount ranges that the present invention limits, the liposome encapsulation of gained liposome was lower than the present invention.
Test example 3 study on the stability
Sample and listing vecuronium bromide for injection freeze-dried powder (lot number: H20100324 with embodiment of the invention 1-3 preparation, Xian Libang Pharmaceutical Co., Ltd.) places respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75%, carry out accelerated test and investigate, experimental result is shown in the following table 4.
Table 4 accelerated test result
As shown in Table 4, when accelerating June, the content of listing preparation and Comparative Examples 1-3, related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, illustrate that product stability of the present invention is good.
The test of test example 4 percolation ratios
Get the sample of test example 1-3 and Comparative Examples 1-3 preparation, at ambient temperature, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on, measure envelop rate, with the dose of sealing in 0 day relatively, calculate percolation ratio, the results are shown in the following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, during long term storage, the vecuronium bromide lipidosome injection percolation ratio for preparing among the embodiment of the invention 1-3 changes little, and the injection percolation ratio for preparing among the Comparative Examples 1-3 increases gradually, the liposome seepage is serious, and the vecuronium bromide lipidosome injection of this explanation the present invention preparation has higher stability.
The mensuration of test example 5 blood drug level
28 rats are divided into 4 groups at random, every group of injection for preparing among drug administration by injection embodiment 1-3 and the Comparative Examples 1-3 respectively, and commercially available vecuronium bromide injection (lot number: H20100324, Xian Libang Pharmaceutical Co., Ltd.), injection volume is the 0.4mg vecuronium bromide.Respectively at 0.5h, 1h, 2h, 4h, 6h, 10h, 15h, 20h and 30h, take a blood sample after the administration, blood sample is measured blood drug level with the HPLC-MS method after treatment.The vecuronium bromide lipidosome injection and the blood drug level of commercially available vecuronium bromide injection and the relation curve of time that prepare among the vecuronium bromide lipidosome injection for preparing among the drafting embodiment 1-3, the Comparative Examples 1-3 are shown in the accompanying drawing 1.
As shown in Figure 1, compare with commercially available vecuronium bromide lipidosome injection with the vecuronium bromide lipidosome injection for preparing among the Comparative Examples 1-3, the vecuronium bromide lipidosome injection for preparing among the embodiment of the invention 1-3 has the following advantages: release rate in vivo slows down, distribution time prolongs in the body circulation, reached improved slow release effect, bioavailability increases.
Industrial applicibility
By the result of above-described embodiment and experimental example as can be known, vecuronium bromide liposome of the present invention has good outward appearance, and granule is little, and particle diameter is even, envelop rate is high, and stability is high, and percolation ratio is low, the time of staying in vivo is long, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not consist of any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because falling within the scope of protection of the present invention.
Each list of references of mentioning among the application or quoting, which is hereby incorporated by reference.
Claims (4)
1. vecuronium bromide lipidosome injection, its composition by following weight proportion is made:
Described vecuronium bromide lipidosome injection adopts following steps to make:
(1) 120g cholesterol, 150g PHOSPHATIDYL ETHANOLAMINE, 30g soybean phospholipid and 10g Tween 80 are dissolved in 1000ml pH and in 7.2 the phosphate buffered saline, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 4g vecuronium bromide, constantly stir the lower 100g of adding trehalose, 70g mannitol and 80g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-30 ℃, and the pre-freeze time is 5 hours, and the distillation time is 48 hours, and baking temperature is 35 ℃, and be 2 hours drying time, namely gets the vecuronium bromide lipidosome injection.
2. vecuronium bromide lipidosome injection, its composition by following weight proportion is made:
Described vecuronium bromide lipidosome injection adopts following steps to make:
(1) pH that 75g cholesterol, 100g PHOSPHATIDYL ETHANOLAMINE, 25g soybean phospholipid and 20g Tween 80 is dissolved in 1000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 4g vecuronium bromide, constantly stir the lower 30g of adding trehalose, 30g mannitol and 40g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-60 ℃, and the pre-freeze time is 2 hours, and the distillation time is 12 hours, and baking temperature is 25 ℃, and be 4 hours drying time, namely gets the vecuronium bromide lipidosome injection.
3. vecuronium bromide lipidosome injection, its composition by following weight proportion is made:
Described vecuronium bromide lipidosome injection adopts following steps to make:
(1) pH that 30g cholesterol, 40g PHOSPHATIDYL ETHANOLAMINE, 10g soybean phospholipid and 10g Tween 80 is dissolved in 1000ml in 7.2 the phosphate buffered saline, makes blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under the aseptic condition, in the liposome of 60 ℃ of molten conditions, add the 2g vecuronium bromide, constantly stir the lower 10g of adding trehalose, 10g mannitol and 30g PVP;
(4) 0.45 μ m filtering with microporous membranes, then fill carries out lyophilizing, and the pre-freeze temperature is-45 ℃, and the pre-freeze time is 3.5 hours, and the distillation time is 25 hours, and baking temperature is 30 ℃, and be 3 hours drying time, namely gets the vecuronium bromide lipidosome injection.
4. each described vecuronium bromide lipidosome injection is in the purposes of preparation in the muscle relaxant according to claim 1-3.
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